US5843905A - Peptidic phosphinyloxymethyl ketones as interleukin-1β-converting enzyme inhibitors - Google Patents
Peptidic phosphinyloxymethyl ketones as interleukin-1β-converting enzyme inhibitors Download PDFInfo
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- US5843905A US5843905A US08/597,346 US59734696A US5843905A US 5843905 A US5843905 A US 5843905A US 59734696 A US59734696 A US 59734696A US 5843905 A US5843905 A US 5843905A
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- aspartic acid
- ketone
- benzyloxycarbonyl
- valyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids R2P(=O)(OH); Thiophosphinic acids, i.e. R2P(=X)(XH) (X = S, Se)
- C07F9/32—Esters thereof
- C07F9/3258—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
- C07F9/3264—Esters with hydroxyalkyl compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
- C07F9/40—Esters thereof
- C07F9/4071—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4075—Esters with hydroxyalkyl compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- This invention relates to a series of novel amino acid, di- and polypeptide analogs which exhibit selective inhibition of interleukin-1 ⁇ -converting enzyme, to compositions containing the novel amino acid analogs and methods for therapeutic utility.
- the interleukin-1 ⁇ -converting enzyme inhibitors described in this invention comprise novel aspartic acid-derived phosphinyloxymethyl ketones which possess particular utility in the treatment of inflammatory and immune-based diseases and cancer.
- Interleukin 1 ⁇ (IL-1 ⁇ ) protease (also known as interleukin 1 ⁇ converting enzyme or ICE) is the enzyme responsible for processing of the biologically inactive 31 kD precursor IL-1 ⁇ to the biologically active 17 kD form (Kostura, M. J.; Tocci, M. J.; Limjuco, G.; Chin, J.; Cameron, P.; Hillman, A. G.; Chartrain, N. A.; Schmidt, J. A., Proc. Nat. Acad. Sci., (1989), 86, 5227-5231 and Black, R. A.; Kronheim, S. R.; Sleath, P. R., FEBS Let., (1989), 247, 386-391).
- IL-1 ⁇ has also been proposed to act as a mediator of a wide variety of diseases, including rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, sepsis, acute and chronic myelogenous leukemia and osteoporosis (Dinarello, C. A.; Wolff, S. M., New Engl. J. Med., (1993), 328, 106).
- a naturally occurring IL-1 ⁇ receptor antagonist has been used to demonstrate the intermediacy of IL-1 ⁇ in a number of human diseases and animal models (Hannum, C. H.; Wilcox, C. J.; Arend, W. P.; Joslin, G.
- WO 9309135 published 11 May 1993, teaches that peptide-based aspartic acid arylacyloxy-and aryoxymethyl ketones are potent inhibitors of ICE in vitro. These compounds also specifically inhibited ICE in the whole cell (in vivo) by their ability to inhibit the formation of mature IL-1 ⁇ in whole cells. These ICE inhibitors also demonstrated utility in reducing fever and inflammation/swelling in rats.
- IL-1 is present in affected tissues in ulcerative colitis in humans.
- IL-1 ⁇ levels correlate with disease severity.
- administration of IL-1ra reduced tissue necrosis and the number of inflammatory cells in the colon. See, Cominelli, F.; Nast, C. C.; Clark, B. D.; Schindler, R., Llerena, R.; Eysselein, V. E.; Thompson, R. C.; and Dinarello, C. A.; "Interleukin-1 Gene Expression, Synthesis, and Effect of Specific IL-1 Receptor Blockade in Rabbit Immune Complex Colitis" J. Clin. Investigations (1990) Vol. 86, pp, 972-980.
- IL-1ra supresses joint swelling in the PG-APS model of arthritis in rats. See Schwab, J. H.; Anderle, S. K.; Brown, R. R.; Dalldorf, F. G. and Thompson, R. C., "Pro- and Anti-Inflammatory Roles of Interelukin-1 in Recurrence of Bacterial Cell Wall-induced Arthritis in Rats". Infect, Immun. (1991) 59; 4436-4442.
- IL-1ra shows efficacy in an small open-label human Rheumatoid Arthritis trial. See, Lebsack, M. E.; Paul, C. C.; Bloedow, C. C.; Burch, F. X.; Sack, M. A.; Chase, W., and Catalano, M. A. "Subcutaneous IL-1 Receptor Antagonist in Patients with Rheumatoid Arthritis", Arth. Rheum. (1991) 34; 545.
- Soluble IL-1 receptor significantly reduces clinically the cutaneous late-phase allergic reaction. This was demostrated in a prospective, randomized, double-blind, placebo-controlled study on 15 allergic subjects. See, Mullarkey, M. F. et al. "Human Cutaneous Allergic Late-Phase Response is Inhibited by Soluble IL-1 Receptor", J. of Immunology, (1994) 152; 2033-2041.
- IL-1 appears to be an autocrine growth factor for the proliferation of chronic myelogenous leukemia cells. Both IL-1ra and slL-1R inhibit colony growth in cells removed from leukemia patients. See, Estrov, Z.; Kurzrock, R.; Wetzler, M.; Kantarjian, H.; Blake, M.; Harris, D.; Gutterman, J. U.; and Talpaz, M., "Supression of Chronic Myelogenous Leukemia Colony Growth by Interleukin-1 (IL-1) Receptor Antagonist and Soluble IL-1 Receptors: a Novel Application for Inhibitors of IL-1 Activity". Blood (1991) 78; 1476-1484.
- the present invention relates to the modulation of processing of IL-1 ⁇ for the treatment of rheumatoid arthritis.
- Levels of IL-1 ⁇ are known to be elevated in the synovial fluid of patients with the disease. Additionally, IL-1 ⁇ stimulates the synthesis of enzymes believed to be involved in inflammation, such as collagenase and PLA 2 , and produces joint destruction which is very similar to rheumatoid arthritis following intra-articular injection in animals.
- a limited number of peptidyl methyl ketone analogs constitute a well-known class of compounds having cysteine protease (papain, cathepsin B) inhibition activity. These peptidyl methyl ketone analogs have been reviewed by D. Rich in Chapter 4 of "Protease Inhibitors", Barrett, A. J. and Salvensen, G. eds., Elsevier, 1986. More recently, ⁇ -aryloxy and ⁇ -arylacyloxy methyl ketones have also been described as inhibitors of cysteine protease (Krantz, A. et al, Biochemistry, 30, p. 4678-4687, 1991).
- n 0-4;
- Y is ##STR2## and when R 3 is OH, then Y can also be ##STR3##
- R 2 is H or deuterium
- R 3 is OH, OR 7 , NR 7 OR 8 or NR 7 R 8 ;
- R 7 and R 8 are independently H, alkyl, cycloalkyl, aralkyl, heteroaralkyl, aryl or heteroaryl;
- R 4 is H or lower alkyl
- R 5 and R 6 are optionally and independently selected from H, OH, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkoxy, aroxy, heteroaroxy, aralkoxy, heteroaralkoxy, alkenyl, aralkenyl or heteroaralkenyl;
- R 5 and R 6 are aryl.
- AA is independently selected from the group consisting of (a) and (b) where (a) is defined as an amino acid of formula II ##STR4## wherein R 7 and R 8 are defined as above and R 9 is (CR 6 R 7 ) 0-6 --R 10 ;
- R 10 is a radical optionally selected from R 11 , where R 11 is described below;
- group (b) is selected from the group consisting of: ##STR5## where W and X are optionally CH 2 , O, S or NR 7 ;
- R 1 is R 10 --CO-- or R 10 SO 2 --, where R 10 is defined previously;
- R 11 is H, alkyl, alkenyl, aryl, heteroaryl, aralkyl, heteroaralkyl, aralkenyl, heteroaralkenyl, hydroxy, alkoxy, 2-(alkyoxy)ethoxy, 2-(alkyoxy)aminoethyl and 2-(alkyoxy)-N-alkylaminoethyl, aralkoxy, heteroaralkoxy, alkylacyloxy, aralkylacyloxy, heteroaralkylacyloxy, aracyloxy, heteroaracyloxy, aryloxyalkylacyloxy, heteroaryloxyalkylacyloxy, alkylacyl, aralkylacyl, heteroaralkylacyl, alkylacylamino, aralkylacylamino, heteroaralkylacylamino, aracylamino, heteroaracylamino, aryloxyalkylacylamino, heteroaryloxyalkylacylamino
- Heteroaryl is defined as an unsubstituted or an optionally substituted mono- or bicyclic ring system of about 5 to about 12 carbon atoms and where each monocyclic ring may possess from 0 to about 4 heteroatoms, and each bicyclic ring may possess about 0 to about 5 heteroatoms selected form N, O, and S provided said heteroatoms are not vicinal oxygen and/or sulfur atoms and were the substituents, numbering from 0 to about 5 may be located at any appropriate position of the ring system and are described by R 11 .
- Examples of such mono- and bicyclic ring systems which are by no means meant to limit the scope of this invention, include benzofuran, benzothiophene, indole, benzopyrazole, coumarin, isoquinoline, pyrrole, thiophene, furan, thiazole, imidazole, pyrazole, triazole, quinoline, pyrollidenone, pyrimidine, pyridine, pyridone, pyrazine, pyridazine, isothiazole, isoxazole and tetrazole.
- the pharmaceutically acceptable salts include both acid and base addition salts.
- acid addition salts refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
- inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like
- organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid
- base addition salts include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts derived from pharmaceutically acceptable organic non-toxic bases which include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaines, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine
- Alkyl is defined as a saturated aliphatic hydrocarbon which may be either straight- or branched-chain or cyclic. Preferred groups have no more than about 12 carbon atoms and may be methyl, ethyl and structural isomers of propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
- Aryl is defined as a phenyl or naphthyl or a substituted phenyl and a substituted naphthyl ring wherein one or more of the hydrogens has been replaced by the same or different substituents as selected from R 11 .
- Alkoxy refers to an alkyl-O-group. For example, methoxy or ethoxy.
- Aryloxy refers to an aryl-O-group. For example, phenoxy.
- Heteroxy refers to a hetero-O-group. For example, 4-pyridyloxy.
- Alkyl refers to an alkyl group substituted by an aryl radical. For example, benzyl.
- Heteroaralkyl refers to an alkyl group substituted by a heteroaryl radical. For example, (4-pyridyl)methyl.
- alkenyl is defined as an unsaturated aliphatic hydrocarbon which may be either straight- or branched-chain or cyclic. Preferred groups have no more than about 12 carbon atoms and no fewer than 2 carbon atoms and contain from one to up to about 6 double bonds. Examples of alkenyl groups include ethenyl, propenyl, 1-hexenyl, 1-3-hexdienyl, 2-methyl-2-butenyl, 2-methyl-3-pentenyl, cyclopentenyl, cyclohexenyl and cyclobutenyl.
- Alkylacyl refers to an alkyl-C(O)-group. For example, acetyl or propionyl.
- Alkylacyloxy refers to an alkyl-C(O)O-group. For example, an acetoxy group.
- Alkylacylamino means alkyl-C(O)--NR 7 where R 7 has been defined previously.
- Alkylacylguanidino means alkyl-C(O)NR 6 C(NR 7 )NH-- where R 6 and R 7 have been defined previously.
- “Ureido” refers to an R 6 R 7 N--C(O)--N--R 6 -group where R 6 and R 7 are described previously.
- Haloalkyl is defined as a saturated aliphatic hydrocarbon of 1-12 carbon atoms which may be either straight- or branched-chain or cyclic and where one or more of the hydrogen atoms is replaced with halogen.
- Preferred haloalkyl groups include trifluoromethyl and pentafluoroethyl.
- Halo means bromo, chloro and fluoro.
- the present invention concerns a method for inhibiting ICE in a mammal by administering a therapeutically effective amount of a compound of the Formula (I) or a pharmaceutical composition containing a compound of the Formula (I) in a pharmaceutically acceptable carrier.
- the method of inhibition is directed for the treatment of IL-1 ⁇ mediated disease states or disorders which include: infectious diseases, such as meningitis and salpingitis; septic shock, respiratory diseases; inflammatory conditions, such as arthritis, cholangitis, colitis, encephalitis, endocerolitis, hepatitis, pancreatitis and reperfusion injury, immune-based diseass, such as hypersensitivity; auto-immune diseases, such as multiple sclerosis; bone diseases; and certain tumors.
- compositions of the present invention comprises an active ingredient of the compound of the formula (I) in admixture with a pharmaceutically acceptable, non-toxic carrier.
- a pharmaceutically acceptable, non-toxic carrier for parenteral (subcutaneous, intraarticular, intramuscular or intravenous) administration, particularly in the form of liquid solutions or suspensions; for oral or buccal administration, particularly in the form of tablets or capsules; or intranasally, particularly in the form of powders, nasal drops or aerosols.
- the compounds When administered orally (or rectally) the compounds will usually be formulated into a unit dosage form such as a tablet , capsule, suppository or cachet.
- a unit dosage form such as a tablet , capsule, suppository or cachet.
- Such formulations typically include a solid, semi-solid or liquid carrier or diluent.
- Exemplary diluents and vehicles are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, mineral oil, cocoa butter, oil of theobroma, alginates, tragacanth, gelatin, syrup, methylcellulose, polyoxyethylene sorbitan monolaurate, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, and magnesium stearate.
- compositions may be prepared by any of the methods well-known in the pharmaceutical art, for example as described in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985.
- Formulations for parenteral administration may contain as common excipients sterile water or saline, alkylene glycols such as propylene glycol, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like.
- Examples of vehicles for parenteral administration include water, aqueous vehicles such as saline, Ringer's solution, dextrose solution, and Hank's solution and nonaqueous vehicles such as fixed oils (such as corn, cottonseed, peanut, and sesame), ethyl oleate, and isopropyl myristate.
- aqueous vehicles such as saline, Ringer's solution, dextrose solution, and Hank's solution
- nonaqueous vehicles such as fixed oils (such as corn, cottonseed, peanut, and sesame), ethyl oleate, and isopropyl myristate.
- Sterile saline is a preferred vehicle and the compounds are sufficiently water soluble to be made up as a solution for all foreseeable needs.
- the vehicle may contain minor amounts of additives such as substances that enhance solubility, isotonicity, and chemical stability, e.g., antioxidants, buffers, and preservatives.
- Formulations for nasal administration may be solid and contain as excipients, for example, lactose or dextran, or may be aqueous or oily solutions for administration in the form of nasal drops or metered spray.
- excipients include sugars, calcium stearate, magnesium stearate, pregelatinated starch, and the like.
- surfactant acids such as for example, glycocholic acid, cholic acid, taurocholic acid, ethocholic acid, desoxycholic acid, chenodesoxycholic acid, dehydrocholic acid, glycodeoxycholic acid, and the like (See, B. H. Vickery, "LHRH and its Analogs-Contraception and Therapeutic Applications", Pt. 2, B. H. Vickery and J. S. Nester, Eds., MTP Press, Lancaster, UK, 1987).
- the active ingredient in amounts between about 0.1 and 100 mg/kg body weight, most preferably from about 0.1 to 30 mg/kg body weight for human therapy, the active ingredient will be administered preferably in the range of from about 0.1 to about 20-50 mg/kg/day.
- This administration may be accomplished by a single administration, by distribution over several applications or by slow release in order to achieve the most effective results.
- administration When administered as a single dose, administration will most preferably be in the range of from about 0.1 to mg/kg to about 10 mg/kg of body weight.
- the compounds of this invention are prepared by one of two related general synthetic methods as described in Schemes 1 and 2.
- the first step of the method involves the synthesis of Z-protected amino acid bromomethyl ketones (formula 2), where the "Z-group” refers to the "benzyloxycarbonyl group".
- Z-group refers to the "benzyloxycarbonyl group”.
- the t-butyl ester bromoketone (formula 2) is reacted with a variety of phosphinic acids. This is conducted by exposing the bromomethyl ketone to an excess of the phosphinic acids in a DMF containing sodium or potassium hydride or potassium fluoride. The reaction can be conveniently monitored by thin layer chromatography (TLC) and once the TLC indicates that the displacement of the bromide with the phosphinic acids is completed, the product is isolated using standard procedures.
- TLC thin layer chromatography
- the desired aspartic acid-based mono-t-butyl ester phosphinyloxymethyl ketones (formula 3) may be purified by conventional methods including recrystallization and silica gel column chromatography. ##STR6## wherein
- AA, R 1 , R 5 , and R 6 are as defined in formula (I) and Z is defined as the benzyloxycarbonyl group.
- the remaining synthetic transformation to generate the ICE inhibitors is hydrolysis of the t-butyl ester function. This is conducted by exposing the ester to a 25% solution of trifluoroacetic acid at 25° C. The de-esterification is usually complete within 3 h and the removal of the volatile TFA and solvent affords the aspartic acid derivative in formula 4. The yield of the reaction is quantitative in most instances, providing the t-butyl ester starting material is of high purity. Purification, if required, can be performed by recrystallization or chromatographic techniques which are well known to those skilled in the art. A solution of 3 molar anhydrous HCl in ethyl acetate may be used in place of TFA-methylene chloride solution with equal efficiency.
- N-terminal amine is then condenced with a carboxylic acid chloride or an active carboxylic acid ("The Practice of Peptide Synthesis", M Bodanszky, Springer-Verlag, N.Y., 1984) to yield an amide (formula 7).
- carboxylic acid chloride or an active carboxylic acid (The Practice of Peptide Synthesis", M Bodanszky, Springer-Verlag, N.Y., 1984) to yield an amide (formula 7).
- t-butyl ester is removed with trifluoroacetic acid to afford the aspartic acid derivative (formula 8).
- phosphinic acids used in the reaction with the bromomethyl ketones can be either purchased from commercial sources or synthesized by adopting known procedures. Their synthesis is readily deduced by those skilled in the art of organic synthesis.
- Part C The HCl-salt obtained in Part B above was dissolved in CH 2 Cl 2 (10 mL), cooled to -20° C. and N- 4-(N,N-dimethylaminomethyl)!benzoyl chloride (4 mmol) was added followed by the addition of 10 mg of dimethylamino pyridine (DMAP) and N-methylmorpholine (5 mmol). The reaction mixture was stirred for 2 hrs at 25° C. The solvent was removed in vacuo and the residue was dissolved in EtOAc (10 mL) which was then washed with water, 0.01 N aqueous HCl, saturated NaHCO 3 , brine and dried over MgSO 4 .
- DMAP dimethylamino pyridine
- Part D The ⁇ -tert-butyl ester obtained in Part C above (1 mmol) was dissolved in trifluoroacetic acid--CH 2 Cl 2 (1:4) and the solution was stirred for 2 hrs at 25° C. The solvent was removed in vacuo and the residue was triturated with ether. The white solid was collected and dried to give the title compound in 90% yield. Mass spectrum: m/z 608 (M+H).
- the 4-(N,N-dimethylaminomethyl) benzoyl chloride was prepared by reacting the acid with excess oxalyl chloride for 1 hr at 25° C.
- the 4-(N,N-dimethylaminomethyl) benzoic acid was in turn prepared from methyl 4-aminomethylbenzoate via reductive alkylation (CH 2 O, Na(OAc) 3 BH as in J. Org. Chem., 1972, 37, 1673) followed by hydrolysis using 10% aqueous NaOH.
- Partially purified IL-1 ⁇ protease is stored at -80° C., thawed on ice, and preincubated for 10 minutes at 37° C. with 2.5 mM dithiothreitol in a buffer solution containing 10 mM Tris-HCl (pH 8.0) and 25% (v/w) glycerol.
- Inhibitors are prepared as stock solutions in dimethyl sulfoxide (DMSO).
- the protease is preincubated with inhibitor in a volume of 20 ⁇ L in a 1.5 mL polypropylene microcentrifuge tube for 15 minutes at 37° C.
- the volume of compound added to the assay is adjusted to yield a DMSO concentration in the preincubation of ⁇ 15% (v/v).
- the enzyme assay is then initiated by the addition of substrate (TRITC-AYVHDAPVRS-NH 2 ) SEQ ID No. 1 to yield a final concentration of 67 ⁇ M in a final volume of 30 ⁇ L.
- the reaction are carried out for 60 minutes at 37° C. in the dark and are terminated by the addition of 10 ⁇ L of 10% trifluoroacetic acid (TFA).
- TFA trifluoroacetic acid
- the samples are analyzed by high pressure liquid chromatography using a reverse phase (C18) column and elution with an acetonitrile/water/TFA gradient. Substrate and product are monitored by their absorbance at 550 nm and elute at 4.2 and 5.2 minutes, respectively.
- the IC50 values recorded for inhibition against the enzyme were ⁇ 10 ⁇ m.
Abstract
Description
__________________________________________________________________________ SEQUENCE LISTING (1) GENERAL INFORMATION: (iii) NUMBER OF SEQUENCES: 1 (2) INFORMATION FOR SEQ ID NO:1: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 10 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: -1 (D) OTHER INFORMATION: /label=TRITC /note= "TRITC is tetramethylrhodamine isothiocyanate". (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 11 (D) OTHER INFORMATION: /label=Xaa /note= "Xaa is NH2". (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 1: AlaTyrValHisAspAlaProValArgSer 1510 __________________________________________________________________________
Claims (8)
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WO2003070229A2 (en) * | 2002-02-22 | 2003-08-28 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Use of proteinase inhibitors in the treatment of autoimmune diseases |
US20060128696A1 (en) * | 2004-05-15 | 2006-06-15 | Annamaria Vezzani | Treating seizures using ice inhibitors |
US7364736B2 (en) | 2001-06-26 | 2008-04-29 | Amgen Inc. | Antibodies to OPGL |
US20080199454A1 (en) * | 2002-02-11 | 2008-08-21 | Michael Mortimore | Caspase inhibitor prodrugs |
EP1992636A2 (en) | 1999-11-12 | 2008-11-19 | Amgen Inc. | Process for correction of a disulfide misfold in Fc molecules |
EP2213685A1 (en) | 2002-09-06 | 2010-08-04 | Amgen Inc. | Therapeutic anti-IL-1R1 monoclonal antibody |
US7928074B2 (en) | 2002-12-30 | 2011-04-19 | Amgen Inc. | Combination therapy with co-stimulatory factors |
US9352010B2 (en) | 2011-07-22 | 2016-05-31 | The J. David Gladstone Institutes | Treatment of HIV-1 infection and AIDS |
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